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REPORT of the Regulatory/HTA/Payer EAP

01|06|2021

Dalia Dawoud, Isabelle TONGIO, Peter Dailey, Pall Jonsson, Colm LEONARD

Session 2

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This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking

under grant agreement No 820755. This Joint Undertaking receives support from the

European Union’s Horizon 2020 research and innovation programme and EFPIA and

bioMérieux SA, Janssen Pharmaceutica NV, Accelerate Diagnostics S.L., Abbott, Bio-Rad

Laboratories, BD Switzerland Sàrl, and The Wellcome Trust Limited.

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Table of contents 1. Summary .......................................................................................................................................... 5

2. Background ...................................................................................................................................... 5

2.1. The Expert Advisory Panel (EAP) ............................................................................................................ 5

2.2. Membership ............................................................................................................................................ 5

2.3. Conduct of meetings ............................................................................................................................... 6

3. Panel Session ................................................................................................................................... 7

3.1. Second EAP session (11 March 2021, webinar virtual meeting ) ........................................................... 7

3.1.1. Attendees ............................................................................................................................................. 7

3.1.2. Requests .............................................................................................................................................. 7

3.2. Detailed EAP discussion and feedback ................................................................................................... 7

3.2.1. VALUE Dx progress............................................................................................................................... 7

3.2.2. COVID 19 and its impacts on diagnostics, AMR and healthcare ......................................................... 8

3.2.3. Epidemiologic and cost data required for the economic evaluation alongside the clinical trials ...... 9

3.2.4. Designing a lifetime health-economic model for respiratory-tract infection diagnostics ................10

4. Appendix ........................................................................................................................................ 13

4.1. VALUE Dx Regulatory/HTA/payer Expert Advisory Panel Session 2: Meeting Minutes .......................13

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1. Summary This report summarises the proceedings of the second session of the Regulatory/HTA/Payer Expert

Advisory Panel (EAP), which aims to advise and support IMI VALUE-Dx in a range of activities to ensure

that the activities and outputs of the project will not only be of the highest scientific quality but will also

have meaningful applicability in the regulatory, HTA and payer contexts. The EAP has been established

under Work Package 5 (WP5) by partner organisations leading and contributing to Task 5.1.

The meeting took place on 11 March 2021 where input on general topics as well as on health economics

focused topics related to WP5 work was provided. This included feedback on the impact of COVID 19 on

the awareness of diagnostics and their value to society.

The next EAP will be held, if required by the consortium, approximately 6 months after this second

meeting.

2. Background

2.1. The Expert Advisory Panel (EAP)

A Regulatory and Health Technology Assessment (HTA) Expert Advisory Panel (EAP) has been established

to ensure the relevance and usability of VALUE Dx activities and outputs to regulators and HTA agencies

throughout the project. The core role will be to inform and advise the activities in work package 5 ensuring

that all relevant perspectives, expertise and concerns are considered. The EAP has the following aims for

the duration of the project:

• Engage actively in discussions, provide feedback and input into topics brought forth by the work

packages, including providing advice on research activities and outputs.

• Ensure that the VALUE Dx outputs are not merely of high scientific quality but will have meaningful

applicability in the regulatory, HTA, and payer contexts.

The EAP consists of individual experts from different European countries with regulatory, HTA (Health

economic), payer or clinical expertise. Some of the experts also have experience in antimicrobial

resistance (AMR) and diagnostics. At the start of the project, it was planned that there would be 5-7

meetings in total over the 4-year period: 3-4 virtual and 2-3 face-to-face meetings.

The Regulatory /HTA/Payer Expert Advisory Panel acts in an advisory capacity within the context of

VALUE-Dx on research, outputs and deliverables. It has no formal legal responsibilities or fiduciary duties

to VALUE-Dx or its partner organisations.

2.2. Membership

The EAP currently has 13 standing members (see below) who are asked to participate in meetings and

input in other tasks such reviewing of documentation and completing surveys using their expertise. NICE

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and the working group for Task 5.1. coordinates all EAP activities. There is some flexibility in the

membership of the EAP with the opportunity to include additional people depending on the needs of the

project.

Expert Advisory Panel members

Name Organisation Stakeholder group/perspective

Colm Leonard (Chair) NICE/NHS Clinical/HTA specialist

Dalia Dawoud (Co-Chair)

NICE HTA /Health Economics

Jordi Carratala

Bellvitge Hospital Clinical specialist

Alec Morton University of Strathclyde Health Economics/HTA

Abigail Colson University of Strathclyde Health Economics/HTA

Marcin Czech Institute of Mother and Child in Warsaw

Health Economics &former Vice-Minister for Health

Rossana Tarricone Bocconi University Health Economics /HTA/healthcare research

Lorenzo Mantovani University of Milano-Bicocca Health economics/health researcher

Wim Goettsch Utrecht University and Zorginstituut Nederland

HTA/HE

Joke Derksen Zorginstituut Nederland HTA

Sun Robin French Ministry of Health Payer

Piet Vancraeynest RIZIV – INAMI

HTA/Payer

Falk Ehmann European Medicines Agency (EMA)- chair of Innovation task force

Regulatory

2.3. Conduct of meetings

Advice is provided on concepts and issues specifically relating to VALUE-Dx. Any feedback/advice that is

provided by members of the EAP is non-binding and will not be recognised as formal Scientific Advice, or

as reflecting the official view or position of the organisations that employ the members of the EAP. All

attending members will maintain confidentiality with meetings run under the principle of Chatham house

rules, according to which information disclosed during a meeting may be reported by those present, but

the source of that information may not be explicitly or implicitly identified. The Panel meetings are open

to the VALUE-Dx Members who can act as observers.

Topics and queries for advice were canvassed by Task 5.1 WG by emailing WP leads and WP 5 task leads

with dates of sessions and request for advice by the EAP. A proforma template was used to give brief

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detail around specific queries to enable theming and ensure correct expertise is available within each

session. The VALUE-Dx Partner requesting advice for selected questions was asked to attend the session

and provide an outline and background on the issue for advice/consideration by the EAP.

3. Panel Session

3.1. Second EAP session (11 March 2021, webinar virtual meeting )

The second panel session of the EAP was held virtually on 11 March 2021, lasting 2 hours. The full panel

session minutes can be found in Annex I. The meeting provided an update on the progress achieved so far

within VALUE Dx. WP5 delivered short presentations on their specific aims, with a focus around clinical

and economic value frameworks including health economics and assessment policy for WP5. The full

presentation is available below.

EAP Session 2 Slides

3.1.1. Attendees

EAP members: Colm Leonard (Chair), Dalia Dawoud (Co-Chair), Alec Morton, Abigail Colson, Marcin Czech,

Lorenzo Mantovani, Sun Robin, Falk Ehmann (n=6)

Value Dx Consortium presenters: Colm Leonard, Jean-Louis Tissier, Herman Goossens, Simon van der Pol, Fernando Antonanzas Session facilitators/attendees with enhanced access: Dalia Dawoud, Maarten Postma, Thea van Asselt, Peter Dailey, Isabelle Tongio, Till Bachmann

3.1.2. Requests

Requests for input were received from WP5 (3 topics: 1 strategic, 2 operational). These were prioritised

by Task 5.1 working group based on time of deliverable, structured content and flow of session. Presenters

provided slides with the aim, context and question for discussion.

3.2. Detailed EAP discussion and feedback

3.2.1. VALUE Dx progress

Herman Goossens (HG) gave a presentation to the Panel about Value Dx progress so far, including

reflecting on the continued impact of COVID-19 on the progress of the project. HG briefly described the

impact of the pandemic on the planned clinical trials which will be conducted within VALUE Dx and the

planned start dates of each of the two trials. HG also provided an update on the progress of the point

prevalence audit surveys (PPAS).

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He also reported that the clinical algorithm (CA) has been developed and validated in WP1, using the large

databases of the patient-level information. Data from the point prevalence survey were all included in the

clinical algorithm, divided by viral and bacterial pathogens. The next steps for this work will focus on

working with WP5 to integrate the cost evaluation assessment into the CA development. Publication of

this CA will be dependent on validation with real-life data, however, little else is seen but COVID-19 at the

moment.

HG also reported that integrated business and sustainability model for VALUE-Dx now completed and

consists of three, closely interconnected parts: sustainable model of clinical networks, business plan for

creating and maintaining a biobank of clinical specimens, strains and DNA and business plan for creating

and maintaining an integrated database. This will be presented and discussed during VALUE-Dx Annual &

General Assembly meeting (30-31 August, Bologna). It will fit under the umbrella of a new organisation

that will be based in the Netherlands and will be launched in summer as the European Clinical Research

Alliance on Infectious Diseases (ECRAID)

3.2.2. COVID 19 and its impacts on diagnostics, AMR and healthcare

COVID-19 has highlighted the importance of Diagnostics through the PCR and antigen tests. In a few

months timeframe, most people have heard about Diagnostics when previously the role and impact of

diagnostics was poorly understood. In addition, rapid procedures have been put in place by policy

makers/healthcare organisations to speed their availability in the market. The EAP were asked to

consider the situation after COVID-19 and make suggestions regarding the possible ways to maintain

this high level of contribution of diagnostics towards populations, public and government bodies and

how it can be translated in a better recognition of the value.

Feedback themes

Country-to-country variation The EAP highlighted that the situation will vary on a country-by-country basis. In the UK, where progress

has been made in controlling the spread of infection and the opening up of schools with the aid of

widespread use of lateral flow testing (LFT), the interest in and awareness of the benefits for diagnostic

tests may well be maintained beyond the pandemic. Alec Morton (AM) also explained that universities

in the UK are considering the widespread use of these tests also to facilitate return to face-to-face

teaching while protecting their employees and students. The experience from the US also showed that

testing can make a difference and help protect students in university communities.

Sun Robin (SR) reflected that the situation in France means that the use of diagnostic tests is continuing

to expand with the move from PCR testing to salivary tests and the move towards the approval of other

diagnostic tests. So, population awareness is also increasing, and this is likely to drive public interest and

influence future attitudes towards adoption of widespread testing. However, Marcin Czech (MC)

reported that situation in Poland was not as favourable as in the UK and France, with increasing number

of cases PCR and antigen testing is still the basis of management practices and no move yet to use LFT.

Fast adoption of new diagnostic technologies The EAP emphasises that the increased awareness as well as simplification of the market access process

may result in faster adoption of new diagnostic technologies in the future. The pandemic has

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accelerated attempts to standardise the laboratory procedures and approval processes in Poland,

according to MC. AM also explained that some organisations will fund the use of rapid diagnostics to

protect themselves against liability. This applies to universities as explained above but it also potentially

spills over to non-COVID testing.

Need for educating the public CL has commented that the pandemic has provided an opportunity to educate the public about diagnostics tests, with basic concepts like sensitivity and specificity being explained in simple terms as is currently being done in the UK by some academic professors in mainstream media and on different social media channels to simplify these concepts and explain to the public.

3.2.3. Epidemiologic and cost data required for the economic evaluation alongside the clinical trials

Fernando Antonanzas (FA) presented 3 operational questions to the EAP relating to the economic

evaluation being undertaken alongside the clinical trials (task 5.3) The question focused on the data

sources required for adapting the model to different countries’ contexts. The first question asked whether

the EAP members’ jurisdiction require cost effectiveness information to make funding decisions, in which

case there would be interest in getting the results of the modelling specific to their jurisdiction. The second

question asked if the EAP members know the key sources of unit costs for health care interventions in

their jurisdictions, particularly the costs of tests. The final question asked the EAP whether they would be

able to facilitate the collection of these unit costs for the items needed in the short-term economic

evaluation of WP5 (Tasks 5.3 and 5.4).

FA gave examples of the unit costs required for the models and these included:

• Costs of diagnostic methods (per test costs, Investment costs (e.g. devices)

• (Additional) testing costs/complimentary explorations

• Emergency room costs

• Visit costs

• PCR costs,

• Microbiology tests in central laboratory costs

• Antiviral treatments costs of each prescribed treatment

• Antibiotic costs of each prescribed treatment

• Symptomatic medication costs (either prescribed or over-the-countrer)

• Time spent by doctors/nurses/pharmacists

• Antibiotic/medicine costs

• Hospitalization costs

• Societal costs (sick leave/productivity losses, informal care, patient travel time)

Additionally, epidemiological data are needed particularly data on the proportion of patients attending

with the conditions relevant to the trial (i.e. with lower respiratory tract infection where cough is the

predominant symptom (<28 days) OR upper respiratory tract infection where symptoms of an acute sore

throat (<14 days) or difficulty swallowing are the dominant symptoms; AND for whom the responsible

clinician is considering or has decided to prescribe an antimicrobial) with respect to the total number of

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patients seen by physicians. This information will give an idea in relation to where the new diagnostic

could be used in medical practice.

Feedback

It was highlighted that some countries have national lists of unit costs (e.g. the Netherlands) while others

do not have such data and this will make it difficult to adapt the model to their jurisdictions. Marcin Czech

(MC) explained that for Poland, the data is available on the national level from National Health Fund

(payer) and the majority of the required unit costs will be available. The epidemiological data would be

more challenging as these are not electronically available within Poland.

AM explained that the UK has these unit costs available on national level. Also, countries that have DRG-

based system for payment should have these data available but how difficult it is to access them will differ.

He also explained cross-country comparisons have their own complexities and it is not straightforward.

FA explained that the main aim is to adapt the model to each country’s jurisdiction rather than

undertaking cross-country comparisons.

3.2.4. Designing a lifetime health-economic model for respiratory-tract infection diagnostics

Simon van der Pol (SvdP) presented 5 operational questions with subpoints in relation to Task 5.4 that is

focused on developing a lifetime economic model to assess the cost effectiveness of rapid diagnostics and

relates to the following aim:

Aim: Develop new health economic models to determine the long-term clinical, public health and economic

impact of diagnostics in terms of AMR prevention with the support of HTAs reflecting the integral value of

diagnostics.

The questions related to the following main topics:

• The demographic model

o What would the panel consider relevant demographic parameters related to community-

acquired respiratory tract infections, besides those already included?

o Consultation data for the emergency room setting is difficult to obtain, does the panel have

ideas on getting data for this setting?

• The consultation model

o Would the panel consider the model structure to be appropriate?

o Assumption: transmission and consultation rates do not change based on the introduction

of point-of-care diagnostics

• The AMR forecasting model

o Does the EAP find it appropriate to forecast AMR based on statistical forecasting methods,

rather than mechanistic dynamic transmission?

o Assumptions:

▪ Number of infections does not change, only the percentage of resistant infections.

▪ Elasticity of 1 between antibiotic consumption and AMR.

o What is the relevance of the following outcomes? :

▪ AMR rates

▪ Clinical effects of future AMR rates

▪ Future AMR-related costs.

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o This will be subject to considerable uncertainty, does the panel have ideas on how to

handle this?

• Outcomes

o What would the panel consider to be other relevant aspects of value we should cover in

this study?

Feedback

The EAP members provided input to each of these questions in turn.

• Demographic model

MC explained that in Poland it will be difficult to provide this data. CL reported that in the UK there is

emergency care data and targets available from the Hospital Episode Statistics (HES). AM commented that

it would be tricky to have this data on the European level and the ECDC would be the first port of call to

get this data. CL also suggested the European Society of Emergency Medicine as a potential source on the

European level.

CL stressed the importance of including smoking status in the model as it affects outcomes for patients.

Vaccination status is another potential characteristic that can be affect outcomes and care provided.

• Consultation model

AM commented that the approach chosen for modelling is an appropriate one, as microsimulation will

allow incorporation of patient characteristics. The assumptions of no change in consultation rates and

transmission were discussed in more detail and the potential of these to be affected due to behaviour

change, and the potential for re-consultation rates to change was also flagged. CL commented that this

assumption may not always hold and can go in either direction, as patients might be encouraged to go to

their GP to get the point of care test. It was also suggested that if the model is flexible to accommodate

assessing the value of using these point of care tests earlier in the disease pathway (e.g. at community

pharmacies), it would be helpful.

• AMR forecasting model

The EAP enquired whether the link between the antibiotic utilisation and AMR levels is based on an

assumption and SvdP explained that it is. Abigail Colson (AC) explained that the team at Strathclyde has

been working in this area using statistical modelling and also expert elicitation. She also explained that

the assumption relating to elasticity will be very much dependent on what else is happening, for example

new clinical guideline recommendations, so there will be a lot of variability around that. AM also

explained that reducing antibiotic consumption on its own is an important aim that governments are now,

and specifically the UK government, are all interested in, so would be an important element of value to

demonstrate. CL explained that it will be important to take into account the effect of the pandemic itself

on the prescribing of antibiotics as there is some evidence of reduced prescribing in certain settings, and

overprescribing of antibiotics in patients admitted to hospital with COVID-19 pneumonia.

• Outcomes

AM reported that an Office of Health Economics (OHE) working paper that discussed the additional value

elements to be considered in the assessment of AMR-related technologies is available and would be a

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valuable source to consult to identify the additional value elements to consider. Environmental impact

was another outcome suggested.

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4. Appendix

4.1. VALUE Dx Regulatory/HTA/payer Expert Advisory Panel Session 2: Meeting Minutes

March 11th- 2-4 pm (GMT)

In attendance

Expert Advisory Panel members

Name Organisation Stakeholder group/perspective

Colm Leonard (Chair) NICE/NHS Clinical HTA specialist

Dalia Dawoud (Co-Chair)

NICE Health Economics/HTA

Alec Morton University of Strathclyde Health Economics/HTA

Abigail Colson University of Strathclyde Health Economics/HTA

Marcin Czech Institute of Mother and Child in Warsaw

Health Economics

Lorenzo Mantovani University of Milano-Bicocca Health economics/health researcher

Sun Robin French Ministry of Health Payer

Falk Ehman European Medicines Agency (EMA)- Head of Innovation task force

Regulatory

Presenters

Name WP

Herman Goossens Value DX lead

Jean-Louis Tissier WP5 lead

Simon van der Pol WP5

Fernando Antonanzas WP5

Session facilitators/attendees with enhanced access

Name Organisation

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Peter Dailey FIND

Isabelle Tongio BioMerieux

Maarten Postma UMCG

Thea van Asselt UMCG

Till Bachmann University of Edinburgh

Meeting Notes

1. Session outline and introductions Colm Leonard (CL- Chair)

Colm Leonard (CL) opened the meeting, welcoming the Expert Advisory Panel (EAP) members to the

second session and giving brief overview of how the panel would operate through the Zoom

environment. CL introduced the new members of the working group that oversees the operational

planning of the EAP meetings: Dalia Dawoud (DD) (NICE) and Peter Dailey (PD) (FIND). He then outlined

the agenda for the session.

2. Update on the progress of Value Dx Herman Goossens (HG)

Herman Goossens (HG) gave a presentation to the Panel about the progress achieved during the last 6

months since the first EAP session. He provided a quick recap of the objectives of ValueDx, the

organisations involved and the nature of the public and private organisation of the consortium, the WP

structures, their inter-dependencies and overall remits/scopes. HG then gave an update on the progress

of the project around the point prevalence audit surveys and their extension due to COVID-19. HG briefly

described plans for the clinical trials which will be conducted within VALUE Dx and flagged the delay in

their starting time due to the impact of the pandemic. He explained that for PRUDENCE trial, recruitment

start date has been postponed from January to September 2021, due to the pressures on primary care

with the continuing COVID-19 pandemic, the vaccine roll-out and lack of flu circulating. The team is also

currently reviewing how to incorporate a BD Veritor™ SARS-CoV-2 test into the diagnostic algorithm for

PRUDENCE with regard to possible varying COVID-19 situations across Europe later this year.

In relation to ADEQUATE trial, HG explained that a data collection process has been completed in close

communication with WP3 and WP5 to build a health-economic framework to assess and demonstrate the

value of diagnostics both for individual patients and for public health impact by reducing antibiotic use

and subsequent antibiotic resistance among patients. He also reported that the first patients are

expected to enrol as of March-April 2021.

3. WP5 objectives and strategic questions Jeal- Louis Tissier (JLT)

EAP

JLT presented a recap of the objectives for Work Package 5 (WP5) which includes clinical and economic

value frameworks including health economics and assessment policy. He then presented a strategic

question to the EAP which is related to the following WP5 aim:

Aim: To develop innovative frameworks to optimise assessment of the clinical and economic value of

diagnostics and facilitate sustainable funding systems over the entire lifetime of the diagnostic.

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Questions asked:

COVID-19 has highlighted the importance of Diagnostics through the PCR and antigen tests. In a few

months, most of people have heard about Diagnostics when previously the role and impact of

diagnostics was poorly understood. In addition, rapid procedures have been put in place by policy

makers/healthcare organisations to speed their availability in the market.

What do you think about the situation after COVID-19? What do you suggest to maintain this high

level of contribution of Diagnostics towards populations, public and government bodies. And how can

it be translated in a better recognition of the value?

The EAP discussed the question posed and provided their opinions. Points of discussion included:

• COVID pandemic continued to place testing and diagnostics in the spotlight. It has increased the

public awareness of the importance of testing to identify asymptomatic cases and reduce

transmission.

• This has been particularly observed due to the reliance on the use of the rapid lateral flow testing

to facilitate reopening society. For example, the reopening of schools in England has relied on

mass testing of students before return to classroom and mandating twice-weekly testing

thereafter as a condition to continued attendance.

4. WP5 - Operational questions Fernando Antonanzas

Fernando Antonanzas (FA) presented 3 questions to the EAP relating to Task 5.3 (Economic evaluation

alongside clinical trial). These related to the specific aim of Value DX to:

1. Aim: Develop health-economic models to determine the short-term economic impact of diagnostics in

terms of AMR prevention with the support of HTAs reflecting the integral value of diagnostics.

The questions were discussed by the EAP and responses provided. A number of suggestions for agencies,

organisations and groups were provided. It was agreed that contact via Email following the meeting

would be the best approach to providing this information to the team.

5. WP5 - Operational questions

Simon van der Pol

Simon van der Pol (SvdP) presented an overview of the epidemiological and economic models being

developed within the context of task 5.4. The following questions relating to the different aspects of the

model development process were posed to the panel members:

• Demographic model

• Consultation model

• Antibiotic resistance forecasting

• Outcomes

The panel members shared their experiences and provided input in relation to each of the

aforementioned questions, and sign-posted the team to other potential sources of information.

6. Close

Colm Leonard (CL)

Dalia Dawoud (DD)

CL thanked all Panellists and presenters for their participation in the second Panel session and DD invited

the panel members to provide their feedback on the running of these sessions and how it can be

improved.

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